Background: In the United States, drug development and approval is a complex process regulated by the Food and Drug Administration under the authority outlined in the Code of Federal Regulation. The goal of this multi-step process is to determine safety and efficacy of new therapeutic entities. Initially, exposure of humans to new therapeutic agents is accomplished in a graded and limited fashion. This approach seeks to minimize risks to study participants from exposure to damaging agents. During early phases, limiting exposure to a few individuals results in the accumulation of preliminary data on pharmacology, short-term toxicity, and efficacy. The inherent limitations of this process necessitate careful critique and caution in extrapolation of phase 1 data.
Objectives: The purpose of this article is to provide a review of the drug approval process focusing on phase 1 trials, which are the earliest human exposure to a new drug. The purpose, variations, and significance of phase 1 trials are described, and a framework is provided to critically evaluate data published from these trials.
Conclusions: Phase 1 trials are primarily designed to accumulate short-term safety (toxicity) and pharmacological data. Although preliminary efficacy may be addressed ("proof of concept" efficacy), it is a secondary endpoint. The numbers of patients are small, the numbers of patients receiving efficacious doses are very small, and controls are absent. Evaluation of efficacy and of long-term toxicity requires longer, larger, and controlled studies.